4A03

Crystal Structure of Mycobacterium tuberculosis DXR in complex with the antibiotic FR900098 and cofactor NADPH

Summary for 4A03

• Entry DOI: 10.2210/pdb4a03/pdb
• Related: 2C82 2JCV 2JCX 2JCY 2JCZ 2JD0 2JD1 2JD2 2Y1C 2Y1D 2Y1E 2Y1F 2Y1G
• Descriptor: 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE, MANGANESE (II) ION, 3-[ethanoyl(hydroxy)amino]propylphosphonic acid, ... (6 entities in total)
• Functional Keywords: oxidoreductase, fr900098, mep pathway
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 2
• Total formula weight: 85489.01

Authors

Bjorkelid, C.,Bergfors, T.,Jones, T.A. (deposition date: 2011-09-07, release date: 2012-01-18, Last modification date: 2023-12-20)

Primary citation

Bjorkelid, C.,Bergfors, T.,Unge, T.,Mowbray, S.L.,Jones, T.A.
Structural Studies on Mycobacterium Tuberculosis Dxr in Complex with the Antibiotic Fr-900098.
Acta Crystallogr.,Sect.D, 68:134-, 2012

PubMed Abstract: A number of pathogens, including the causative agents of tuberculosis and malaria, synthesize the essential isoprenoid precursor isopentenyl diphosphate via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway rather than the classical mevalonate pathway that is found in humans. As part of a structure-based drug-discovery program against tuberculosis, DXR, the enzyme that carries out the second step in the MEP pathway, has been investigated. This enzyme is the target for the antibiotic fosmidomycin and its active acetyl derivative FR-900098. The structure of DXR from Mycobacterium tuberculosis in complex with FR-900098, manganese and the NADPH cofactor has been solved and refined. This is a new crystal form that diffracts to a higher resolution than any other DXR complex reported to date. Comparisons with other ternary complexes show that the conformation is that of the enzyme in an active state: the active-site flap is well defined and the cofactor-binding domain has a conformation that brings the NADPH into the active site in a manner suitable for catalysis. The substrate-binding site is highly conserved in a number of pathogens that use this pathway, so any new inhibitor that is designed for the M. tuberculosis enzyme is likely to exhibit broad-spectrum activity.

PubMed: 22281742
DOI: 10.1107/S0907444911052231

Experimental method

X-RAY DIFFRACTION (1.65 Å)